Project Summary The hippocampus plays a critical role in the formation of episodic memories. The current predominant hypothesis is that memories are gradually established across distributed cortical networks under the in?uence of hippocampal activity. However, our understanding of the nature and extent of hippocampal in?uences on cortical circuits remains incomplete. Part of the challenge has been that any subthreshold modulation of cortical neurons is inaccessible to extracellular recordings, which have been the main tool for studying of cortico-hippocampal interactions. We propose to combine whole-cell recordings in auditory cortex (AC) with optogenetic control of the projections to this area from the hippocampal complex (HC), in order to quantify the in?uence of the HC-AC projections on the membrane potential dynamics of individual cortical neurons as a function of brain state and learning. We aim to use this approach to identify cortical neurons that receive direct hippocampal input, and characterize their properties and the plasticity of the corresponding synapses in vivo. Finally, we aim to use optogenetic perturbations of the HC-AC projections during learning events and hippocampal ripples to establish the functional role of these projections in memory formation, and to study the timing of their participation in the consolidation process. Quantifying the subthreshold modulation of cortical neurons by hippocampal inputs can provide sensitive measures of the functional coupling between these areas and bring us closer to a mechanistic understanding of their interactions and their role in memory formation.